Takotsubo syndrome and COVID‐19: A systematic review

Abstract Background and Aims Takotsubo syndrome (TTS), also known as stress cardiomyopathy, is characterized by acute and transient left ventricular dysfunction and has increased during the COVID‐19 pandemic. Herein, we aim to review studies on TTS that were associated with COVID‐19 infection, vaccine, and other COVID‐19‐related etiologies including psychosocial stressors. Methods We systematically searched PubMed, EMBASE, and Scopus up to May 12, 2022. We included case reports, case series, and original articles that reported at least one TTS case associated with COVID‐19, or TTS cases after receiving COVID‐19 vaccines, or TTS cases secondary to psychological stress due to the COVID‐19 pandemic. The quality assessment was conducted using the Joanna Briggs Institute checklist. Results Sixty‐seven articles including 102 cases were included. Hypertension was the most frequently accompanying comorbidity (N = 67 [65.6%]) and the mean left ventricular ejection fraction was 36.5%. Among COVID‐19 patients, the in‐hospital mortality rate was 33.3%. On the other hand, only one COVID‐19‐negative individual expired (2.3%). The most common presenting clinical symptom was dyspnea in 42 (73.6%) patients. the mean time interval from the first symptom to admission was 7.2 days. The most common chest imaging finding was ground‐glass opacity which was reported in 14 (31.1%) participants. The most common abnormalities were T‐wave inversion in 35 (43.2%) and ST‐segment elevation in 30 (37%). Brain natriuretic peptide and troponin were elevated in 94.7% and 95.9% of participants, respectively. Conclusion The TTS in patients with COVID‐19 is almost rare, whereas it could lead to a great mortality and morbidity. An individual with COVID‐19, especially an elderly woman, presented with dyspnea in addition to a rise in brain natriuretic peptide and troponin should be evaluated for TTS.


| INTRODUCTION
Takotsubo syndrome (TTS) also known as stress cardiomyopathy is characterized by acute and transient left ventricular dysfunction without coronary obstruction. 1 It is reported to be often triggered by physical or emotional triggers. 1 The clinical presentation of TTS closely imitates that of acute coronary syndrome, which most patients present with chest pain, show ST-segment elevation on electrocardiogram (ECG), and mild increase in serum troponin levels. 2 Due to a similar clinical picture of TTS and acute coronary syndrome, distinguishing the two conditions still remains crucial; therefore, ischemic cardiomyopathies have to be excluded before TTS diagnosis. 2 Although TTS is often reversible, it can lead to acute heart failure, left ventricle outflow tract obstruction, cardiogenic shock, thrombosis formation, and arrhythmias. 3 Recently, studies have reported an increase in TTS incidence during the COVID-19 pandemic. 4 A retrospective cohort study indicated that acute coronary syndrome resulting from stress cardiomyopathy was found to be higher during the pandemic period (7.8%) compared to similar periods before the pandemic (1.5%-1.8%). 5 These observations suggested viral mechanism associated with COVID-19 causing TTS, as well as an increase in TTS in the pandemic due to the associated psychological, social, and economic stress derived from imposed restrictive measures. Therefore, the severe acute respiratory syndrome coronavirus disease 2 (SARS-CoV-2) infection potentially induces physical and psychosocial stress in patients, which may lead to an increase in the risk of TTS development. 6 Although the underlying pathophysiology of COVID-19-induced TTS still remains unclear, some mechanisms have been proposed in this regard. Direct viral myocardial injury, downregulation of angiotensin-converting enzyme 2 receptors in myocardium, cytokine storm, surge in catecholamines, and vascular inflammation are proposed to be associated with cardiac injury. [7][8][9][10] Moreover, studies also reported TTS and other cardiomyopathies in non-COVID-19 patients after receiving the mRNA-based and other vaccines despite the low reported rate of cardiovascular complications. 11 A previous systematic review evaluated the effects of COVID-19 in development of TTS using case reports in 2020. 12 The study did not evaluate the effects of COVID-19 vaccination in the development of TTS and its results need to be updated. Hence, in this systematic review, we aimed to review studies on TTS that were associated with COVID-19 infection, vaccine, and other COVID-19related etiologies including psychosocial stressors. The findings could be helpful for clinicians and health authorities for prevention and management of TTS in the COVID-19 pandemic.
which are providing the inclusion criteria, methods of condition measurement, validity of the diagnostic methods, consecutive inclusion of participants, completeness of participants' inclusion, reporting of the demographic characteristics, clinical information, outcomes, presenting clinic demographic information and the quality of the statistical analysis. 16 The JBI checklist for cohort studies includes 11 items, which are similarity of the two groups, similarity in measurement of exposures, validity and reliability of measuring exposure, identifying confounders, stating strategies for dealing with confounders, lacking of the outcomes at the start of the study, validity and reliability of outcome measurement, completeness and sufficient duration of follow-up time, using strategies to address incomplete follow-up, and using appropriate statistical analysis. 17 A higher quality score represents a better quality of that study in the JBI checklists.

| RESULTS
A total of 1064 studies were identified. After applying the eligibility criteria and title and abstract review followed by detailed evaluations, 67 articles were selected. 4,5,9,11, Of these articles, 46 were centered around TTS in patients with COVID-19, 13 were related to TTS in patients with emotional triggering events, and 8 were linked to TTS in patients with recent COVID-19 vaccination ( Figure 1).
All articles were written in English. Thirty (44.7%) were from the United States. The details on the study characteristic of included articles are represented in Table 1. A total of 102 patients were included in this review which comprised three groups. The first group consists of 60 patients (58.8%) with confirmed COVID-19 diagnosis, the second group consisted of 34 cases (33.3%) with known emotional triggering events, and the third group consisted of 8 cases (7.8%) who had recently received COVID-19 vaccination. The mean age of the reported cases was 67.2 (SD = 12.6; range 30-94) years with a female predominance of 68.6%. Among women with TTS, data on patients' age was available in 57 cases, of which 78.9% were above 60 years of age. Hypertension was the most frequently accompanying comorbidity (N = 67 [65.6%]), followed by dyslipidemia (N = 38 [37.2%]) and diabetes (N = 26 [25.4%]). Data on the left ventricular ejection fraction (LVEF) were reported in 60 cases. The overall mean LVEF was 36.5% (males: 37.2% and females: 36.2%) ( Table 1). Among COVID-19 patients, the in-hospital mortality rate was 33.3%. On the other hand, only one COVID-19-negative individual was expired (2.3%) ( Table 1).
Regarding cardiac biomarkers, BNP was measured in 38 cases and was found to be elevated in 36 (94.7%). Troponin was measured in 74 cases and was found to have been raised in 71 (95.9%). Also, CK was measured in 28 cases and found to be raised in 14 (50%) ( Table 3).
Neurologic or psychiatric disorders (i.e., multiple sclerosis, cerebrovascular accident, dementia, schizophrenia, anxiety, depression, chronic pain syndrome, obstructive sleep apnea, and Bickerstaff brainstem encephalitis) were reported in 16/82 cases (19.5%) ( Table 4). Among the case reports, the quality scores ranged from 5 to 8, in which 41 articles had the complete scores and providing the demographic characteristics and diagnostic tests were the items with the highest quality (Supporting Information: Table S2). Among the case series, the scores ranged from 6 to 10 with an average of 7.4.
Validity of measuring the condition, consecutive, and complete inclusion of participants were those with the lowest quality in the included articles (Supporting Information: Table S3). The cohort study received the highest score for all of the items (Supporting Information: Table S4).

| DISCUSSION
The findings of the present study showed that the most common comorbidities and clinical presentation among those with TTS and COVID-19 were hypertension and dyspnea, respectively. Moreover, the most common ECG findings of patients with COVID-19 who developed TTS were ST elevation and T inversion. Elevated troponin, followed by BNP were the cardiac biomarkers which had the highest frequency among the patients. TTS leads to complications in which cardiogenic shock is the most common one. Comparing the patients with TTS after COVID-19 infection and those with conventional TTS associated with emotional triggers shows that the most common presentation in the former group is dyspnea, some of them need mechanical ventilation, and the most common complication is cardiogenic shock, while in the latter group they mostly presented with chest pain, there is no need for mechanical ventilation, and the frequency of complications is lower.
In accordance with our study which found that most cases of TTS were developed in patients with COVID-19 above 60 years of age, a systematic review conducted by Singh et al. 12 on 12 case reports of TTS in patients with COVID-19 showed a mean age of 70.8 years and 66.6% had age of above 60 years old. Moreover, the TTS was more common among women with COVID-19 than males (66.6% vs. 33.4%), 16 as it was also revealed in our study (69.5% vs. 30.5%). The same study also showed that hypertension (66.7%), followed by diabetes (41.6%), and dyslipidemia (16.6%) were the most common comorbidities. 12 Similarly, we found that hypertension with a frequency of 65% was the most common comorbidity in these patients. The study also showed a mean time interval of 8.3 days from the first clinical presentation to admission which was almost in accordance with our study that was 7.2 days. 12 In addition, Haussner et al. 81 82 In patients receiving mRNA COVID-19 vaccines which lead to cardiac consequences, the most common signs/ symptoms were chest pain (96.1%) and fever (38.2%). 83 TTS can also clinically be presented with chest pain and dyspnea. 84 Although most of the studies reported almost similar frequency in clinical presentations, minor differences could be as a result of differences in mean age, sex, and underlying diseases of the patients included in the different studies.
The ST-T abnormalities, in particular ST-segment elevation, were the most common ECG finding in patients with COVID-19. 85 Moreover, TTS could lead to occurrence of ST-segment abnormalities. 86 Diffuse ST elevation (43.8%) followed by PR depression In echocardiography, the mean LVEF was 36.4% and the GGO feature was reported in CXR of 31.9% of participants with COVID-19 who developed TTS. In this regard, Singh et al. 12 reported a mean 40.6% of LVEF of included 12 patients, and bilateral opacities (72.7%) and GGO (54.5%) were the most frequent findings in CXR. 12 The minor differences between the studies could be as a result of higher number of included cases in our study than the previously conducted one in 2020. 12

CONFLICT OF INTEREST
The authors declare no conflict of interest.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.

ETHICS STATEMENT
Since the ethical approval and the Institutional Review Board (IRB) were reported for each of the included studies, no additional ethical or IRB approvals were required for this systematic review.

TRANSPARENCY STATEMENT
The lead author Mahan Shafie affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.